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Updated: Jul 2, 2026

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07:18

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Published on: October 27, 2011

FET proteins and PARylation-dependent condensates promote replication fork reversal and genome stability

Celeste Giansanti1, Jack C Schultz1, Jessica Jackson2

  • 1Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.

Nature Communications
|June 30, 2026
PubMed

Insights

PARG inhibition impacts cancer therapy by affecting DNA repair. FET proteins, like FUS, are recruited to replication forks, influencing DNA replication dynamics and genome stability.

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • Genomics

Background:

  • Targeting DNA repair pathways, particularly ADP-ribosylation controlled by PARP1/2 and PARG, is a key cancer therapeutic strategy.
  • The precise mechanisms by which Poly(ADP-ribose) glycohydrolase (PARG) inhibition affects DNA replication are not fully understood.

Purpose of the Study:

  • To investigate the impact of acute PARG inhibition on DNA replication fork dynamics.
  • To elucidate the role of FET family proteins in replication stress response and genome stability.

Main Methods:

  • Isolation of Proteins on Nascent DNA (iPOND) coupled with quantitative proteomics.
  • Functional assays to assess replication fork progression, reversal, and DNA damage.
  • Analysis of gene inactivation effects on genome stability and synthetic lethality.

Main Results:

  • PARG inhibition recruits FET family proteins (FUS, EWS, TAF15) to replication forks in a PAR-dependent manner.
  • FET protein condensates slow replication fork progression and promote fork reversal.
  • FUS inactivation results in unrestrained fork progression, increased DNA gaps, genome instability, and synthetic lethality with BRCA1 deficiency.

Conclusions:

  • FET protein assemblies are crucial modulators of replication stress responses.
  • These findings highlight FET proteins as key regulators of genome stability and cellular responses to PARP-targeting cancer therapies.

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